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Reg4 protects against acinar cell necrosis in experimental pancreatitis
  1. Guoyong Hu1,
  2. Jiaqing Shen2,
  3. Li Cheng2,
  4. Chuanyong Guo1,
  5. Xuanfu Xu1,
  6. Feng Wang2,
  7. Li Huang1,
  8. Lijuan Yang2,
  9. Miao He3,
  10. Di Xiang3,
  11. Shunying Zhu3,
  12. Mingyuan Wu3,
  13. Yan Yu4,
  14. Wei Han3,
  15. Xingpeng Wang1
  1. 1Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
  2. 2Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  3. 3Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
  4. 4Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai, China
  1. Correspondence to Professor Dr X P Wang, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301Yanchang Road, Shanghai, 200072, China; wangxp1965{at}yahoo.com.cn

Abstract

Background and aims Reg4 is a recently discovered member of the regenerating gene family with distinctive expression profiles in primary cancers. To date, the physiological function of Reg4 is poorly understood. Previously, the authors found that Reg4 was markedly upregulated during acute pancreatitis (AP). The aim of this study was to investigate the role of Reg4 in experimental pancreatitis.

Methods AP was induced in C57BL/6 mice by administration of either l-arginine or caerulein, and Reg4 expression was assessed by immunofluorescence, reverse transcriptase (RT)-PCR and western blot analyses. Recombinant human Reg4 protein (rReg4), heat-inactivated Reg4, neutralising antibody and vehicle were also administered to mice by subcutaneous injection. The severity of AP was determined by measuring amylase and lipase activities in the serum and histological grading. The effect of rReg4 on cell death was examined and epidermal growth factor receptor (EGFR), p-EGFR, Akt, p-Akt, Bcl-2 and Bcl-xL expression were assessed by western blot analysis of isolated murine acinar cells treated with l-arginine.

Results Reg4 mRNA and protein were markedly upregulated during arginine-induced pancreatitis. Reg4 was widely expressed in residual acinar cells around the islets and regenerating metaplastic epithelium. rReg4 could protect against arginine-induced necrosis of acinar cells both in vivo and in vitro. This protective effect was also confirmed in the caerulein-induced murine model of AP. It was shown that arginine induced expression of Bcl-2 and Bcl-xL, while rReg4 upregulated Bcl-2 and Bcl-xL expression by activating the EGFR/Akt pathway. The upregulation of Bcl-xL correlated inversely with cell necrosis in isolated pancreatic acinar cells.

Conclusions The data suggest that Reg4 may protect against acinar cell necrosis in experimental pancreatitis by enhancing the expression of Bcl-2 and Bcl-xL via activation of the EGFR/Akt signalling pathway.

  • Pancreatitis
  • Reg4
  • necrosis
  • Bcl-2
  • Bcl-xl
  • family proteins
  • cell death
  • pancreatic damage
  • pancreatic pathology
  • pancreatitis

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Footnotes

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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